Our cells face numerous membrane-stress inducing factors that are potentially detrimental. Indeed, invading pathogens, protein aggregates, silica crystals, lysosomotrophic agents and even vaccine particles entering the cell through endocytosis cause membrane stress. Left unchecked such stress can lead to permeabilization and rupture of endolysosomal compartments and unloading of content into the cytosol, allowing toxic hydrolytic enzymes to cause damage and inflict cell death. A small protein originally associated with autophagy, ATG8, is central to the cell defense against such insults in a process coined non-canonical autophagy (NCA).Herein, the NCA machinery detects membrane insults and mediates protection in a process involving conjugation of ATG8 proteins to the affected membrane. Importantly, NCA defects give rise to a number of detrimental disease - causing effects, including compromised ability to handle invading pathogens, to clear away dead cells by phagocytosis (a cause of auto-immune diseases) and to maintain functional secretory granules (Crohn's disease ( CD)). However, the molecular mechanisms linking NCA to cellular protection are not well understood.
We aim to provide a better understanding of the molecular events in NCA, the mechanisms of the conjugation / de-conjugation machinery and the downstream events that mediate protection.